title: miR-34a expression, epigenetic regulation, and function in human placental diseases.
abstract: Preeclampsia (PE) is the major pregnancy-induced hypertensive disorder responsible for maternal and fetal morbidity and mortality that can be associated with intrauterine growth restriction (IUGR). PE and IUGR are thought to be due to a placental defect, occurring early during pregnancy. Several placental microRNAs (miRNAs) have been shown to be deregulated in the context of placental diseases and could thus play a role in the pathophysiology of PE. Here, we show that pri-miR-34a is overexpressed in preeclamptic placentas and that its placental expression is much higher during the first trimester of pregnancy than at term, suggesting a possible developmental role. We explored pri-miR-34a regulation and showed that P53, a known activator of miR-34a, is reduced in all pathological placentas and that hypoxia can induce pri-miR-34a expression in JEG-3 cells. We also studied the methylation status of the miR-34a promoter and revealed hypomethylation in all preeclamptic placentas (associated or not with IUGR), whereas hypoxia induced a hypermethylation in JEG-3 cells at 72 h. Despite the overexpression of pri-miR-34a in preeclampsia, there was a striking decrease of the mature miR-34a in this condition, suggesting preeclampsia-driven alteration of pri-miR-34a maturation. SERPINA3, a protease inhibitor involved in placental diseases, is elevated in IUGR and PE. We show here that miR-34a overexpression in JEG-3 downregulates SERPINA3. The low level of mature miR-34a could thus be an important mechanism contributing to SERPINA3 upregulation in placental diseases. Overall, our results support a role for miR-34a in the pathophysiology of preeclampsia, through deregulation of the pri-miRNA expression and its altered maturation.
authors.affiliation: INSERM U1016; Institut Cochin; Paris, France; CNRS UMRS 8104; Paris, France; Université Paris Descartes; Paris, France.
authors.forename: Ludivine
authors.initials: L
authors.lastname: Doridot
authors.affiliation: INSERM U1016; Institut Cochin; Paris, France; CNRS UMRS 8104; Paris, France; Université Paris Descartes; Paris, France.
authors.forename: Dorothée
authors.initials: D
authors.lastname: Houry
authors.affiliation: INSERM U1016; Institut Cochin; Paris, France; CNRS UMRS 8104; Paris, France; Université Paris Descartes; Paris, France.
authors.forename: Harald
authors.initials: H
authors.lastname: Gaillard
authors.affiliation: INSERM U1016; Institut Cochin; Paris, France; CNRS UMRS 8104; Paris, France; Université Paris Descartes; Paris, France.
authors.forename: Sonia T
authors.initials: ST
authors.lastname: Chelbi
authors.affiliation: INSERM U1016; Institut Cochin; Paris, France; CNRS UMRS 8104; Paris, France; Université Paris Descartes; Paris, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Barbaux
authors.affiliation: INSERM U1016; Institut Cochin; Paris, France; CNRS UMRS 8104; Paris, France; Université Paris Descartes; Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Vaiman
mesh_terms: D045744:Cell Line, Tumor; D002822:Choriocarcinoma / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D010922:Placenta Diseases / Q000235:genetics / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D015843:Serpins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014594:Uterine Neoplasms / Q000235:genetics / Q000378:metabolism
chemical_list: C522425:MIRN34 microRNA, human; D035683:MicroRNAs; C516148:SERPINA3 protein, human; D015843:Serpins; D016159:Tumor Suppressor Protein p53
keywords: SERPINA3; intra-uterine growth restriction; mir34a; placenta; preeclampsia